HIV/AIDS is a global pandemic with nearly 40 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We have established population-based cohorts in Uganda, Zambia, Malawi, South Africa, India, China, and the U.S. In the Rakai district of Uganda, we had previously demonstrated that male circumcision reduced the risk of HIV infection in the general population by nearly 60%. We therefore conducted a randomized clinical trial of circumcision to prevent HIV acquisition among men. Of 4,996 uncircumcised, HIV-negative men aged 15 to 49 years of age, 2,474 were randomly assigned to circumcision whereas 2,522 were randomized to delayed circumcision after 24 months of follow-up. HIV incidence was 0.66 % among circumcised men, and 1.33 % in the uncircumcised group, an estimated efficacy of 51%. The as-treated protective efficacy of circumcision was 55% and increased to 60% in those followed for 24 months. Genital ulcer disease was also reduced by 50%. Sexual behaviors were similar in both groups. Moderate or severe adverse events occurred in 3.6% of the circumcised men, all of which resolved with appropriate therapy. On the basis of this and two other circumcision trials in Kenya and South Africa, the WHO and UNAIDS have strongly endorsed male circumcision to reduce HIV acquisition in men internationally. In a cost-effectiveness model, the cost per infection averted was estimated to be $1,269 depending on the efficacy of circumcision for either or both sexes and assuming 75% service coverage. In addition, male circumcision would reduce the reproductive rate to < 1, effectively controlling the epidemic.[unreadable] Among women in Rakai, we documented that HIV acquisition is significantly higher during pregnancy than during the post-partum period. We subsequently observed a decline in fertility with increasing HIV viral load in women. This is particularly accentuated in viral loads > 4.5log10 copies/ml. These findings suggest that antiretroviral therapy may also increase the fertility rate among HIV-infected women. In a study to determine rates of progression by HIV subtype, we examined 349 HIV-1 seroconverters. Subtype distribution was 59% D, 15% A, 21% recombinant and 4% multiple viral subtypes. Median time to AIDS was shorter for subtype D, recombinant, and multiple subtypes (6.5, 5.6, and 5.8 years, respectively) compared with subtype A (8 years). Progression to death was significantly higher for subtype D, recombinant, and multiple subtypes compared to A. In analysis of subtype D, we determined that over 25% of subtype D expressed CXCR4 tropism, which was associated with the increased progression rate. In a related study of subtype B in 67 MACS participants, we documented that 52% of men exhibited dual or mixed tropism at one or more timepoints. The earliest detection of X4 virus was at 12 months post-seroconversion. X4 tropism was detected more frequently in those who progressed to AIDS than those who did not. The appearance of X4 tropism also correlated with the onset of T-cell decline and development of AIDS.[unreadable] With the scale-up of antiretroviral drugs in Africa, we have examined the predictors of long-term survival and viral failure among Ugandan children and adults. In a study of 526 adults and 250 children on first-line ART regimens, children were twice as likely to have viral failure compared to adults. The sole independent predictor of viral failure was use of D4T/3TC/Nevaripine vs. AZT/3TC/Efavirenz. In children the independent predictors of viral failure included male gender, baseline CD4, and treatment with D4T/3TC/NVP. All patients with viral breakthrough had NNRTI and 3TC-associated mutations. Of those individuals with detectable plasma HIV RNA, 65% had treatment interruptions of > 48 hours and accounted for 90% of missed doses. Adherence is an important predictor of survival with full viral suppression in these studies. In a separate study in Kampala, Uganda, of 500 patients started on ART, approximately 10% had detectable viral loads after two years of treatment. Treatment interruption for more than two days and a 30% fall from peak CD4 count were the only parameters independently associated with viral failure. A monitoring algorithm using either adherence or CD4 parameters as a screen for viral failure would require viral load testing of 23% of patients and would not detect 33% of patients with elevated viral loads. In a community-based study also in Uganda of 258 patients initially started on antiretroviral therapy, 86% had an undetectable viral load. The median CD4 increase for active patients was 197 cells/mm3. Patients with a history of antiretroviral use and lack of CD4 cell response were more likely to experience virologic failure. Overall, 85% of patients were still on ARVs at one year and 73% at two years. Survival was 84% at one year and 82% at two years. An integrated, comprehensive program based on peer health workers and nurses which incorporates the delivery of antiretrovirals with personal, family, and community services provides a model of excellence for improved AIDS care. [unreadable] In studies in Lusaka, Zambia, we examined the efficacy of measles vaccination in children born to HIV-infected mothers. HIV-infected infants had lower levels of passively acquired antibodies to measles at birth than uninfected children. By nine months 99% of all children had antibody levels < 50 mIU/ml. Of 696 children aged 2 to 8 months who received measles vaccine, 88% of the HIV-infected children developed antibody levels compared to 94% of the seronegative children. However, by 27 months after vaccination, only half of the HIV-infected children who survived and returned for follow-up maintained measles antibody levels compared to 92% of the uninfected children. This study demonstrates that HIV-infected children will show a good primary antibody response to measles vaccine, but rapid waning of antibody suggests that measles vaccinations may need to be repeated more frequently in areas of high HIV prevalence. In a follow-up of these children at three years, 39% of the 105 children who were HIV infected had died compared to only a 1.6% mortality of HIV seronegative children. Anemia and percent CD4 T-lymphocytes < 15% were significantly associated with mortality among the HIV-infected children. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.